Tat Protein Induces Human Immunodeficiency Virus Type 1 (HIV-1) Coreceptors and Promotes Infection with both Macrophage-Tropic and T-Lymphotropic HIV-1 Strains

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Journal of Virology, November 1998, p. 8952-8960, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Tat Protein Induces Human Immunodeficiency Virus Type 1 (HIV-1) Coreceptors and Promotes Infection with both Macrophage-Tropic and T-Lymphotropic HIV-1 Strains

Lili Huang,¹^,²^,^* Irene Bosch,¹^,² Wolfgang Hofmann,³^,⁴ Joseph Sodroski,³^,⁴ and Arthur B. Pardee¹^,²

Divisions of Cancer Biology¹ and Human Retrovirology,³ Dana-Farber Cancer Institute, and Departments of Biological Chemistry and Molecular Pharmacology² and Pathology,⁴ Harvard Medical School, Boston, Massachusetts 02115

Received 27 May 1998/Accepted 6 August 1998

Chemokine receptors CCR5 and CXCR4 are the primary fusion coreceptors utilized for CD4-mediated entry by macrophage (M)- andT-cell line (T)-tropic human immunodeficiency virus type 1 (HIV-1)strains, respectively. Here we demonstrate that HIV-1 Tat protein,a potent viral transactivator shown to be released as a solubleprotein by infected cells, differentially induced CXCR4 and CCR5expression in peripheral blood mononuclear cells. CCR3, a lessfrequently used coreceptor for certain M-tropic strains, was alsoinduced. CXCR4 was induced on both lymphocytes and monocytes/macrophages,whereas CCR5 and CCR3 were induced on monocytes/macrophages butnot on lymphocytes. The pattern of chemokine receptor inductionby Tat was distinct from that by phytohemagglutinin. Moreover,Tat-induced CXCR4 and CCR5 expression was dose dependent. Monocytes/macrophageswere more susceptible to Tat-mediated induction of CXCR4 and CCR5than lymphocytes, and CCR5 was more readily induced than CXCR4.The concentrations of Tat effective in inducing CXCR4 and CCR5expression were within the picomolar range and close to the rangeof extracellular Tat observed in sera from HIV-1-infected individuals.The induction of CCR5 and CXCR4 expression correlated with Tat-enhancedinfectivity of M- and T-tropic viruses, respectively. Taken together,our results define a novel role for Tat in HIV-1 pathogenesisthat promotes the infectivity of both M- and T-tropic HIV-1 strainsin primary human leukocytes, notably in monocytes/macrophages.

^* Corresponding author. Mailing address: Division of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA02115. Phone: (617) 632-4688. Fax: (617) 632-4680. E-mail: lhuang{at}mbcrr.harvard.edu.

Journal of Virology, November 1998, p. 8952-8960, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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